Dihydrophthalazine antagonists of excitatory amino acid receptors

ABSTRACT

Substituted dihydrophthalazine compositions are provided which are active as non-NMDA ionotropic excitatory amino acid (EAA) receptor antagonists. The compositions are useful for treating disorders associated with excessive activation of the non-NMDA subtype of the ionotropic EAA receptor. The compounds further are useful as testing agents to identify and characterize other compounds for the treatment of these disorders. The compounds are useful therapeutically as sedatives or for the treatment of neurosychopharmacological disorders such as stroke, ischemia and epilepsy. The compositions may be provided in combination with a suitable carrier for oral or parenteral administration. The compounds may be administered orally or parenterally for the treatment of a variety of disorders associated with non-NMDA EEA receptor function.

This application is a continuation-in-part of U.S. Ser. No. 08/476,272,filed Jun. 7, 1995, by Jeffrey C. Pelletier, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to dihydrophthalazine compounds useful asantagonists of excitatory amino acid receptors.

During the past fifteen years a great deal of attention has beendirected toward the excitatory amino acids (EAA's), glutamate andaspartate, since they are believed to be the neurotransmittersresponsible for the fast excitatory transmission in the mammaliancentral nervous system. The ionotropic EAA receptors are generallysub-classified into NMDA and non-NMDA receptors. These classificationsare defined by those receptors which preferentially bindN-methyl-D-aspartate (NMDA) and those that are not responsive to NMDAbut responsive to α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid(AMPA) or kainic acid (KA).

Tarnawa et al, describe 2,3-benzodiazepines (Eur. J. Pharmacol.,167:193-199, 1989) which inhibit AMPA stimulated currents in neuronalcells. The 2,3-benzodiazepines such as GYKI 52466 and 53655 described byTarnawa are non-competitive AMPA antagonists which bind to a novelmodulatory site on the AMPA receptor. Meldrum (Stroke, 23:861, 1992 &Brain Res., 571:115, 1992) has shown that GYKI 52466 is effective in ratmodels of both global and focal ischemia. GYKI 52466 was effective in amiddle cerebral artery occlusion (MCAO) model of ischemia when giveneither continuously for 2 hours just after occlusion or delayed for onehour. The compounds reduced cortical infarct volumes by 68% and 48%respectively. In another model of neurodegenerative disease, GYKI 52466was as effective as the glutamate site competitive antagonist NBQX inrat common carotid arteries model of global ischemia. These two animalmodels suggest that these compounds may be useful for the treatment ofstroke and neurodegenerative ischmic conditions.

Efforts to find NMDA receptor antagonists and blockers which areneuroprotective have been very successful while efforts to find specificnon-NMDA receptor antagonists have been much less successful. A numberof pharmaceutical companies have pursued development of ion channelblockers or full antagonists of the NMDA receptor to protect againstboth chronic and acute neurodegenerative processes. Although somecompounds have entered clinical trials, there has been only limitedprogress in developing a clinically useful NMDA receptor antagonist.Though non-NMDA antagonists have been shown to be useful inneuroprotective models in animals, there has been no progress indeveloping a clinically useful AMPA receptor antagonist.

It is an object of the invention to provide compounds which are usefulas non-NMDA glutamate receptor antagonists as well as methods for theirsynthesis. It is a further object of the invention to provide non-NMDAreceptor antagonists which are useful as sedatives or for the treatmentof neuropsychopharmacological disorders such as stroke, ischemia andepilepsy. It is yet another object of the invention to provide compoundswhich are useful for the treatment of neurological, neuropsychiatric,neurogenerative and functional disorders associated with excessiveactivation of the non-NMDA subtypes of the ionotropic EAA receptor.

SUMMARY OF THE INVENTION

Compositions are provided which are active as non-NMDA ionotropicexcitatory amino acid (EAA) receptor antagonists, in particular, whichbind to the KA and/or AMPA receptors, and which therefore are useful fortreating disorders associated with excessive activation of the non-NMDAsubtypes of the ionotropic EAA receptors. The compounds further areuseful as testing agents to identify and characterize other compoundsfor the treatment of these disorders.

Illustrative compounds include:

4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-ethylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(3-Aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,and

4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-propylthiocarbamoyl-6,7-methylenedioxyphthalazine.

The compositions may be provided in combination with a suitable carrierfor oral or parenteral administration. The compounds may be administeredorally or parenterally for the treatment of a variety of disordersassociated with non-NMDA glutamate receptor function. The compositionsmay be used, for example, as sedatives or for the treatment ofneuropsychopharmacological disorders such as stroke, ischemia andepilepsy.

DETAILED DESCRIPTION OF THE INVENTION

I. Glossary of Terms

The term "antagonist" as used herein means any compound which reducesthe flow of cations through the non-NMDA receptor.

The term "neuropsychopharmacological disorder" as used herein means adisorder resulting from or associated with an excessive flux of ionsthrough the AMPA receptor ligand-gated cation channels, and includeschemical toxicity (including substance tolerance and addiction),excitotoxicity, neurodegenerative disorders (such as Huntington'sdisease, Parkinson's disease, and Alzheimer's disease), post-strokesequelae, epilepsy, seizures, mood disorders (such as bipolar disorder,dysthymia, and seasonal affective disorder), and depression.Neurodegenerative disorders can result from dysfunction or malfunctionof the AMPA receptor.

The term "NMDA receptor" as used herein means a receptor which isstimulated, at a minimum, by the excitatory amino acids glutamic acid aswell as by NMDA, but is not stimulated by AMPA or KA. It is aligand-gated receptor.

The term "AMPA receptor" as used herein means a receptor which isstimulated, at a minimum, by the excitatory amino acids glutamic acid aswell as by AMPA, but is not stimulated by NMDA. It is a ligand-gatedreceptor.

The term "Kainate receptor" as used herein means a receptor which isstimulated, at a minimum, by the excitatory amino acids glutamic acid aswell as by KA, but is not stimulated by NMDA or AMPA. It is aligand-gated receptor.

Pharmaceutically acceptable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences 171th Edition, p. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hygroscopicity andsolubility.

Throughout this application when an alkyl substituent is identified, thenormal alkyl structure is intended (i.e. butyl is n-butyl) unlessotherwise specified. However, when radicals are identified (e.g. R⁵),both branched and straight chains are included in the definition ofalkyl, alkenyl, and alkynyl.

II. Compositions With Non-NMDA Receptor Antagonist Properties

A. Compounds of Formula I

Compounds of Formula I are provided which are active as non-NMDAionotropic EAA receptor antagonists. ##STR1## wherein R¹, R², R³ and R⁴are independently

a) H,

b) HO,

c) R¹¹ O--,

d) halogen (F, Cl, Br),

e) C1-C3-alkyl,

f) CF3,

g) R¹² CO₂ --, or

h) R¹² CONH--;

R¹ and R², or R² and R³, or R³ and R⁴ can be taken together to be

a) --OCH₂ O--, or

b) --OCH₂ CH₂ O--;

R⁵ and R⁶ are independently

a) H,

b) C1-C6-alkyl,

c) C3-C6-alkenyl,

d) C3-C6-alkynyl,

e) C3-C6-cycloalkyl,

f) phenyl or substituted phenyl, where the phenyl is substituted withone or two substituents, C1-C3-alkyl, halogen (F, Cl, Br), R¹² HN--, R¹²O--, CF₃ --, R¹¹ SO₂ -- or CO₂ R¹², or

g) phenyl-C1-C3-alkyl or substituted phenyl-C1-C3-alkyl, where thephenyl is substituted with one or two substituents, C1-C3-alkyl, halogen(F, Cl, Br), R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂ -- or , CO₂ R¹² ;

R⁵ and R⁶ taken together can be C3-C6-cycloalkyl;

R⁷ is

a) R¹³ R¹⁴ NCO--,

b) R¹³ R¹⁴ NCS--,

c) R¹³ R¹⁴ NC(NR¹²)--,

d) R¹⁵ OCO--

e) R¹³ CO--

f) R¹³ R¹⁴ NCH₂ CO--,

g) R¹² O₂ C--(CH₂)_(n) --,

h) R¹³ R¹⁴ NCO--(CH₂)_(n) --,

i) NC--(CH₂)_(n) --,

j) H,

k) C1-C6 alkyl,

l) C1-C6-perfluoroalkyl,

m) C3-C6-alkenyl,

n) C3-C6-alkynyl, or

o) C3-C6-cycloalkyl;

R⁶ and R⁷ taken together can be

a) --(CH₂)_(m) CH₂ (R¹³)NCO--,

b) --(CH₂)_(m) CH₂ OCO--, or

c) --(CH₂)_(m) CH₂ CH₂ CO--;

R⁸ and R⁹ are independently

a) H,

b) R¹³ R¹⁴ N--,

c) R¹³ NHC(NH),

d) R¹² HNOC--, or

e) R¹² CONH--;

R¹⁰ is

a) H,

b) C1-C3-alkyl,

c) halogen (F, Cl, Br),

d) R¹² HN--,

e) R¹² O--,

f) CF₃ --, or

g) CO₂ R¹² ;

R¹¹ is C1-C3-alkyl;

R¹² is H or C1-C3-alkyl;

R¹³ and R¹⁴ are independently

a) H,

b) C1-C10-alkyl,

c) C1-C6-perfluoroalkyl,

d) C3-C10-alkenyl,

e) C3-C10-alkynyl, or

f) C3-C6-cycloalkyl;

R¹³ and R¹⁴ taken together can be C3-C6-cycloalkyl;

R¹⁵ is C1-C6-alkyl, C3-C6-alkenyl, or C3-C6-cycloalkyl;

n is 1 to 6;

m is 0 to 2;

and pharmaceutically acceptable salts thereof;

wherein R⁸ and R⁹ cannot both be H.

Preferred compounds are compounds of Formula I wherein:

R¹, R², R³ and R⁴ are independently H, R¹¹ O--, halogen (F, Cl, Br), orC1-C3-alkyl;

R² and R³ taken together can be --OCH₂ O--;

R⁷ is

a) R¹³ R¹⁴ NCO--,

b) R¹³ R¹⁴ NC(NR¹²)--,

c) R¹⁵ OCO--,

d) R¹³ CO--,

e) R¹³ R¹⁴ NCS--, or

f) H;

R⁸ and R⁹ are independently H, H₂ N--, or CH₃ CONH--;

and pharmaceutically acceptable salts thereof.

Specifically preferred are:

4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-ethylcarbamoyl-6,7methylenedioxyphthalazine,

4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(3-aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,

4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylthiocarbamoyl-6,7-methylenedioxyphthalazine,and

4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylenedioxyphthalazine.

The compounds of Formula I may be combined with a suitablepharmaceutical carrier and used to treat neurological,neuropsychological, neuropsychiatric, neurodegenerative,neuropsychopharmacological and functional disorders associated withexcessive activation of the non-NMDA subtype of the ionotropic EAAreceptors. The compounds can also be used as testing agents to identifyand characterize other compounds for the treatment of acute and chronicneurodegenerative diseases, seizures, depression, anxiety and substanceaddiction.

B. Compounds of Formula II

In another embodiment, compounds of Formula II are provided which areactive as non-NMDA ionotropic EAA receptor antagonists. ##STR2## whereinR¹, R², R³ and R⁴ are independently

a) H,

b) HO,

c) R¹¹ O--,

d) halogen (F, Cl, Br),

e) C1-C3-alkyl,

f) CF₃,

g) R¹² CO₂ --, or

h) R¹² CONH--;

R¹ and R², or R² and R³, or R³ and R⁴ can be taken together to be

a) --OCH₂ O--, or

b) --OCH₂ CH₂ O--;

R⁵ is

a) H,

b) C1-C6-alkyl,

c) C3-C6-alkenyl,

d) C3-C6-alkynyl,

e) C3-C6-cycloalkyl,

f) phenyl or substituted phenyl, where the phenyl is substituted withone or two substituents selected from the group C1-C3-alkyl, halogen (F,Cl, Br), R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂ -- or CO₂ R¹², and

g) phenyl-C1-C3-alkyl or substituted phenyl-C1-C3-alkyl, where thephenyl is substituted with one or two substituents selected from thegroup C1-C3-alkyl, halogen (F, Cl, Br), R¹² HN--, R¹² O--, CF₃ --, R¹¹SO₂ -- or CO₂ R¹² ;

R¹¹ is C1-C3-alkyl;

R¹² is H or C1-C3-alkyl;

R¹⁶ or R¹⁷ are independently

a) H,

b) C1-C3-alkyl,

c) halogen (F, Cl, Br),

d) R¹² O--,

e) CF₃ --, or

f) --CO₂ R¹² ;

R¹⁸ and R¹⁹ are independently

a) H,

b) R¹³ R¹⁴ N--,

c) R¹³ NHC(NH), or

d) R¹² COHN--;

and pharmaceutically acceptable salts thereof, with the proviso that R¹⁸and R¹⁹ cannot both be H.

Preferred compounds are compounds of Formula II wherein:

R¹, R², R³ and R⁴ are independently H, R¹¹ O--, halogen (F, Cl, Br), orC1-C3-alkyl;

R² and R³ taken together can be --OCH₂ O--;

R¹⁸ and R¹⁹ are independently H, NH₂ or CH₃ CONH--;.

and pharmaceutically acceptable salts thereof.

Specifically preferred are:

1-(3-aminophenyl)-6,7-methylenedioxyphthalazine,

1-(3-amino-4-methylphenyl)-6,7-methylenedioxyphthalazine,

1-(3-amino-4-chlorophenyl)-6,7-methylenedioxyphthalazine,

1-(3-aminophenyl)-6-methoxyphthalazine,

1-(3-amino-4-methylphenyl)-6-methoxyphthalazine,

1-(3-amino-4-chlorophenyl)-6-methoxyphthalazine

1-(4-aminophenyl)-6,7-methylenedioxyphthalazine,

1-(4-acetylaminophenyl)-6,7-methylenedioxyphthalazine,

4-(4-aminophenyl)-1-methyl-6,7-methylenedioxyphthalazine,

4-(4-acetylaminophenyl)-1-methyl-6,7-methylenedioxyphthalazine,

1-(4-aminophenyl)-7-methoxyphthalazine,

1-(4-acetylaminophenyl)-7-methoxyphthalazine,

4-(4-aminophenyl)-1-methyl-7-methoxyphthalazine, and

4-(4-acetylaminophenyl)-1-methyl-7-methoxyphthalazine.

The compounds of Formula II may be combined with a suitablepharmaceutical carrier and used to treat neurological,neuropsychological, neuropsychiatric, neurodegenerative,neuropsychopharmacological and functional disorders associated withexcessive activation of the non-NMDA subtype of the ionotropic EAAreceptors. The compounds can also be used as testing agents to identifyand characterize other compounds for the treatment of acute and chronicneurodegenerative diseases, seizures, depression, anxiety and substanceaddiction.

III. Synthesis

The compounds of Formula I or II may be prepared using syntheticreactions and techniques available in the art, as described, for examplein March, "Advanced Organic Chemistry," 4th Edition, 1992,Wiley-Interscience Publication, New York. The reactions are performed insolvent suitable to the reagents and materials employed and suitable forthe transformation being effected. Depending upon the synthetic routeselected, and the functionality of the starting material orintermediates, the appropriate protection groups and deprotectionconditions available in the art of organic synthesis may be utilized inthe synthesis of the compound.

In one embodiment, compounds of Formula I may be synthesized as outlinedin Scheme 1. Protected aldehydes 3 can be prepared from commerciallyavailable aldehydes or aldehydes known in the literature by halogenatingthe aldehyde by treatment with bromine in a solvent such as acetic acidat a temperature from 0° to 35° C. for 6-24 hours. The aldehyde is thenprotected by a group such as an acetal by treatment of 2 with an alcoholsuch as ethylene glycol or ethanol in an inert solvent such as toluenewith a ##STR3## catalytic amount of an acid such as p-toluensulfonicacid at the reflux temperature of the mixture with an apparatus toremove the water.

Protected amides 7 can be prepared from appropriate acids or acidchlorides by treatment of the acid chloride or acid anhydride withN,O-dimethylhydroxylamine in an inert solvent such as methylene chlorideor tetrahydrofuran and a base such a pyridine at a temperature of -10°to 0° C. for 1-8 hours. Amides 6 can be converted to anilines byreducing the nitro group by treatment of 5 with hydrogen and a catalystsuch a 10% Pd/C or 5% Pt/C in a solvent such as methanol at a pressurefrom atmospheric pressure to 60 psi for 30 minutes to 6 hours. Theaniline 6 can be protected as the imine by treatment with a ketone sucha benzophenone or an imine such as benzophenone imine in an inertsolvent such as toluene with an acid catalyst such as boron trifluorideat a temperature from 20° C. to the reflux of the solvent for 2-8 hours.

The substituted benzophenones 8 are prepared by reacting the lithiatedderivative of 3, which is generated by reacting 3 with a reagent such asn-butyl lithium in an inert solvent such as tetrahydrofuran at atemperature of -110° to -45° C. for 10-60 minutes, with amides 7 at atemperature of -78° to 25° C. for 2-24 hours. The benzophenones 8 arethen converted to phthalazines 9 by treatment with hydrazine orhydrazine hydrochloride in a solvent such as methanol at a temperatureof 0° to 35° C. for 6-24 hours. The phthalazine anilines 9 are protectedby treatment with an amine protecting group such as acetic anhydrideeither neat or in an inert solvent such as tetrahydrofuran at atemperature of 0° C. to reflux of the solvent for 2-12 hours.

The dihydrophthalazines 11 are prepared by reacting protectedphthalazine 10 with an alkyl lithium or Grignard reagent in an inertsolvent such as tetrahydrofuran at a temperature of -78° to 25° C. for1-6 hours. The dihydrophthalazines 11 can then be treated with anacylating reagent such as acid chloride, an alkylisocyanate, analkylisothiocyanate, an alkylchloroformate or chloroamidate in an inertsolvent such as methylene chloride with a base such as dimethylaminopyridine (DMAP) at a temperature of 0° C. to reflux of the solvent for6-48 hours. The acetanilide protecting group can then be removed bycareful treatment with an base such as NaOH in a solvent such asmethanol at a temperature of 25° C. to reflux of the mixture for 2-72hours.

Exemplary compounds of Formula I, Examples 1-135, which can be preparedusing the above methods, as shown in Scheme 1 above, by using theappropriate starting materials and reagents, are listed below inTable 1. The synthesis of Examples 1, 2, 3, 4, 11, 23 and 31 isdescribed below. ##STR4##

                                      TABLE 1                                     __________________________________________________________________________    Receptor Antagonists of Formula I.                                            EX.                                                                              R.sup.1, R.sup.2, R.sup.3, R.sup.4                                                      R.sup.5, R.sup.6                                                                    R.sup.7   R.sup.8, R.sup.9 R.sup.10                                                             Anal.                                    __________________________________________________________________________    1  6,7-methylenedioxy                                                                      Me, H MeNHCO    4-NH.sub.2                                                                            NMR, IR                                  2  6,7-methylenedioxy                                                                      Me, H EtNHCO    4-NH.sub.2                                                                            NMR, IR                                  3  6,7-methylenedioxy                                                                      Me, H nPrNHCO   4-NH.sub.2                                                                            NMR, IR                                  4  6,7-methylenedioxy                                                                      Me, H iPr NHCO  4-NH.sub.2                                                                            NMR, IR                                  5  6,7-methylenedioxy                                                                      Me, H nBuNHCO   4-NH.sub.2                                                                            NMR, IR                                  6  6,7-methylenedioxy                                                                      Me, H sBuNHCO   4-NH.sub.2                                       7  6,7-methylenedioxy                                                                      Me, H tBuNHCO   4-NH.sub.2                                                                            NMR, IR                                  8  6,7-methylenedioxy                                                                      Me, H cyclopropylNHCO                                                                         4-NH.sub.2                                       9  6,7-methylenedioxy                                                                      Me, H C.sub.6 H.sub.13 NHCO                                                                   4-NH.sub.2                                       10 6,7-methylenedioxy                                                                      Me, H H.sub.2 NCO                                                                             4-NH.sub.2                                       11 6,7-methylenedioxy                                                                      Et, H MeNHCO    4-NH.sub.2                                                                            NMR, IR                                  12 6,7-methylenedioxy                                                                      n-Bu, H                                                                             EtNHCO    4-NH.sub.2                                       13 6,7-methylenedioxy                                                                      Me, Me                                                                              EtNHCO    4-NH.sub.2                                       14 6,7-methylenedioxy                                                                      cyclopropyl                                                                         EtNHCO    4-NH.sub.2                                       15 6,7-methylenedioxy                                                                      cyclohexyl                                                                          EtNHCO    4-NH.sub.2                                       16 6,7-methylenedioxy                                                                      CH3, H                                                                              EtNHCO    4-NH.sub.2                                       17 6,7-methylenedioxy                                                                      Me, H MeCO      4-NH.sub.2                                                                            NMR, IR                                  18 6,7-methylenedioxy                                                                      Me, H EtCO      4-NH.sub.2                                       19 6,7-methylenedioxy                                                                      Et, H EtCO      4-NH.sub.2                                       20 6,7-methylenedioxy                                                                      n-Bu, H                                                                             EtCO      4-NH.sub.2                                       21 6,7-methylenedioxy                                                                      Me, Me                                                                              EtCO      4-NH.sub.2                                       22 6,7-methylenedioxy                                                                      cyclopropyl                                                                         EtCO      4-NH.sub.2                                       23 6,7-methylenedioxy                                                                      Me, H MeOCO     4-NH.sub.2                                                                            NMR, IR                                  24 6,7-methylenedioxy                                                                      Me, H EtOCO     4-NH.sub.2                                       25 6,7-methylenedioxy                                                                      Et, H EtOCO     4-NH.sub.2                                       26 6,7-methylenedioxy                                                                      n-Bu, H                                                                             EtOCO     4-NH.sub.2                                       27 6,7-methylenedioxy                                                                      Me, H PhOCO     4-NH.sub.2                                       28 6,7-methylenedioxy                                                                      cyclopropyl                                                                         EtOCO     4-NH.sub.2                                       29 6,7-methylenedioxy                                                                      Me, H iPrNHCO   4-NH.sub.2                                       30 6,7-methylenedioxy                                                                      Me, H nPrNHCO   4-NH.sub.2                                       31 6,7-methylenedioxy                                                                      Me, H Me.sub.2 NCO                                                                            4-NH.sub.2                                                                            NMR, IR                                  32 6-methoxy Me, H Me.sub.2 NCO                                                                            4-NH.sub.2                                       33 6-methoxy Me, H Et.sub.2 NCO                                                                            4-NH.sub.2                                       34 6-methoxy Et, H Me.sub.2 NCO                                                                            4-NH.sub.2                                       35 6-methoxy n-Bu, H                                                                             Me.sub.2 NCO                                                                            4-NH.sub.2                                       36 6-methoxy Me, Me                                                                              Me.sub.2 NCO                                                                            4-NH.sub.2                                       37 6-methoxy cyclopropyl                                                                         Me.sub.2 NCO                                                                            4-NH.sub.2                                       38 6-methoxy cyclohexyl                                                                          Me.sub.2 NCO                                                                            4-NH.sub.2                                       39 6-methoxy CH3, H                                                                              Me.sub.2 NCO                                                                            4-NH.sub.2                                       40 6-methoxy Me, H MeCO      4-NH.sub.2                                       41 6-methoxy Me, H EtCO      4-NH.sub.2                                       42 6-methoxy Et, H EtCO      4-NH.sub.2                                       43 6-methoxy n-Bu, H                                                                             EtCO      4-NH.sub.2                                       44 6-methoxy Me, Me                                                                              EtCO      4-NH.sub.2                                       45 6-methox.y                                                                              cyclopropyl                                                                         EtCO      4-NH.sub.2                                       46 6-methoxy Me, H MeOCO     4-NH.sub.2                                       47 6-methoxy Me, H EtOCO     4-NH.sub.2                                       48 6-methoxy Et, H EtOCO     4-NH.sub.2                                       49 6-methoxy n-Bu, H                                                                             EtOCO     4-NH.sub.2                                       50 6-methoxy Me, Me                                                                              EtOCO     4-NH.sub.2                                       51 6-methoxy cyclopropyl                                                                         EtOCO     4-NH.sub.2                                       52 6-methoxy Me, H iPrNHCO   4-NH.sub.2                                       53 6-methoxy Me, H nPrNHCO   4-NH.sub.2                                       54 6,7-methylenedioxy                                                                      Me, H MeNHCO    3-NH.sub.2                                       55 6,7-methylenedioxy                                                                      Me, H EtNHCO    3-NH.sub.2                                       56 6,7-methylenedioxy                                                                      Me, H nPrNHCO   3-NH.sub.2                                       57 6,7-methylenedioxy                                                                      Me, H nBuNHCO   3-NH.sub.2                                       58 6,7-methylenedioxy                                                                      Me, H MeCO      3-NH.sub.2                                       59 6,7-methylenedioxy                                                                      Me, H MeNHCO    3-MeO,4-NH.sub.2                                 60 6,7-methylenedioxy                                                                      Me, H EtNHCO    3-MeO,4-NH.sub.2                                 61 6,7-methylenedioxy                                                                      Me, H MeCO      3-MeO,4-NH.sub.2                                 62 6,7-methylenedioxy                                                                      Me, H EtCO      3-MeO,4-NH.sub.2                                 63 6,7-methylenedioxy                                                                      Me, H EtCO      3-NH.sub.2                                       64 6,7-methylenedioxy                                                                      Me, H MeNHCO    3-Cl,4-NH.sub.2                                  65 6,7-methylenedioxy                                                                      Me, H EtNHCO    3-Cl,4-NH.sub.2                                  66 6,7-methylenedioxy                                                                      Me, H MeCO      3-Cl,4-NH.sub.2                                  67 6,7-methylenedioxy                                                                      Me, H EtCO      3-Cl,4-NH.sub.2                                  68 6-methoxy Me, H EtNHCO    4-NH.sub.2                                       69 6-methoxy Me, H nBuNHCO   4-NH.sub.2                                       70 6-methoxy-7-chloro                                                                      Me, H EtNHCO    4-NH.sub.2                                       71 6-methoxy-7-chloro                                                                      Me, H nPrNHCO   4-NH.sub.2                                       72 7-methoxy Me, H EtNHCO    4-NH.sub.2                                       73 7-methoxy Me, H nPrNHCO   4-NH.sub.2                                       74 6-chloro-7-methoxy                                                                      Me, H EtNHCO    4-NH.sub.2                                       75 6-chloro-7-methoxy                                                                      Me, H nPrNHCO   4-NH.sub.2                                       76 6-methoxy-7-methyl                                                                      Me, H nPrNHCO   4-NH.sub.2                                       77 6,7-methylenedioxy                                                                      Me, H MeNHCS    4-NH.sub.2                                       78 6,7-methylenedioxy                                                                      Me, H EtNHCS    4-NH.sub.2                                       79 6,7-methylenedioxy                                                                      Me, H nPrNHCS   4-NH.sub.2                                                                            NMR, IR                                  80 6,7-methylenedioxy                                                                      Me, H iPr NHCS  4-NH.sub.2                                       81 6,7-methylenedioxy                                                                      Me, H nBuNHCS   4-NH.sub.2                                       82 6,7-methylenedioxy                                                                      Me, H sBuNHCS   4-NH.sub.2                                       83 6,7-methylenedioxy                                                                      Me, H tBuNHCS   4-NH.sub.2                                       84 6,7-methylenedioxy                                                                      Me, H cyclopropylNHCS                                                                         4-NH.sub.2                                       85 6,7-methylenedioxy                                                                      Me, H C.sub.6 H.sub.13 NHCS                                                                   4-NH.sub.2                                       86 6,7-methylenedioxy                                                                      Me, H H.sub.2 NCS                                                                             4-NH.sub.2                                       87 6,7-methylenedioxy                                                                      Et, H MeNHCS    4-NH.sub.2                                       88 6,7-methylenedioxy                                                                      n-Bu, H                                                                             EtNHCS    4-NH.sub.2                                       89 6,7-methylenedioxy                                                                      Me, Me                                                                              EtNHCS    4-NH.sub.2                                       90 6,7-methylenedioxy                                                                      cyclopropyl                                                                         EtNHCS    4-NH.sub.2                                       91 6,7-methylenedioxy                                                                      cyclohexyl                                                                          EtNHCS    4-NH.sub.2                                       92 6,7-methylenedioxy                                                                      CH3, H                                                                              EtNHCS    4-NH.sub.2                                       93 6,7-methylenedioxy                                                                      Me, H MeNHCO    3-NH.sub.2                                       94 6,7-methylenedioxy                                                                      Me, H EtNHCO    3-NH.sub.2                                       95 6,7-methylenedioxy                                                                      Me, H nPrNHCO   3-NH.sub.2                                       96 6,7-methylenedioxy                                                                      Me, H iPrNHCO   3-NH.sub.2                                       97 6,7-methylenedioxy                                                                      Me, H nBuNHCO   3-NH.sub.2                                       98 6,7-methylenedioxy                                                                      Me, H sBUNHCO   3-NH.sub.2                                       99 6,7-methylenedioxy                                                                      Me, H tBuNHCO   3-NH.sub.2                                       100                                                                              6,7-methylenedioxy                                                                      Me, H cyclopropylNHCO                                                                         3-NH.sub.2                                       101                                                                              6,7-methylenedioxy                                                                      Me, H C.sub.3 H.sub.16 NHCO                                                                   3-NH.sub.2                                       102                                                                              6,7-methylenedioxy                                                                      Me, R H.sub.2 NCO                                                                             3-NH.sub.2                                       103                                                                              6,7-methylenedioxy                                                                      Et, H MeNHCO    3-NH.sub.2                                       104                                                                              6,7-methylenedioxy                                                                      nBu, R                                                                              EtNHCO    3-NH.sub.2                                       105                                                                              6,7-methylenedioxy                                                                      Me, Me                                                                              EtNHCO    3-NH.sub.2                                       106                                                                              6,7-methylenedioxy                                                                      cyclopropyl                                                                         EtNHCO    3-NH.sub.2                                       107                                                                              6,7-methylenedioxy                                                                      cyclohexyl                                                                          EtNHCO    3-NH.sub.2                                       108                                                                              6,7-methylenedioxy                                                                      CH.sub.3, H                                                                         EtNHCO    3-NH.sub.2                                       109                                                                              H,H,H,H   Me, H MeNHCO    4-NH.sub.2                                       110                                                                              H,H,H,H   Me, H EtNHCO    4-NH.sub.2                                       112                                                                              H,H,H,H   Me, H nPrNHCO   4-NH.sub.2                                       113                                                                              H,H,H,H   Me, H iPrNHCO   4-NH.sub.2                                       114                                                                              H,H,H,H   Me, H nBuNHCO   4-NH.sub.2                                       115                                                                              H,H,H,H   Me, H sBuNHCO   4-NH.sub.2                                       116                                                                              H,H,H,H   Me, H tBuNHCO   4-NH.sub.2                                       117                                                                              H,H,H,H   Me, H cyclopropylNHCO                                                                         4-NH.sub.2                                       118                                                                              H,H,H,H   Me, H C.sub.6 H.sub.13 NHCO                                                                   4-NH.sub.2                                       119                                                                              H,H,H,H   Me, H H.sub.2 NCO                                                                             4-NH.sub.2                                       120                                                                              H,H,H,H   Et, H MeNHCO    4-NH.sub.2                                       121                                                                              H,H,H,H   n-Bu, H                                                                             EtNHCO    4-NH.sub.2                                       122                                                                              H,H,H,H   Me, Me                                                                              EtNHCO    4-NH.sub.2                                       123                                                                              H,H,H,H   cyclopropyl                                                                         EtNHCO    4-NH.sub.2                                       124                                                                              H,H,H,H   cyclohexyl                                                                          EtNHCO    4-NH.sub.2                                       125                                                                              H,H,H,H   CH.sub.3 , H                                                                        EtNHCO    4-NH.sub.2                                       126                                                                              6,7-methylenedioxy                                                                      Me, H H         4-CH.sub.3 CONH                                                                       NMR, IR                                  127                                                                              6,7-methylenedioxy                                                                      Et, H H         4-CH.sub.3 CONH                                  128                                                                              6,7-methylenedioxy                                                                      n-Bu, H                                                                             H         4-CH.sub.3 CONH                                  129                                                                              6,7-methylenedioxy                                                                      Me, Me                                                                              H         4-CH.sub.3 CONH                                  130                                                                              6,7-methylenedioxy                                                                      cyclopropyl                                                                         H         4-CH.sub.3 CONH                                  131                                                                              6,7-methylenedioxy                                                                      Me, H H         4-NH.sub.2                                       132                                                                              6,7-methoxy                                                                             Me, H H         4-CH.sub.3 CONH                                  133                                                                              6,7-methoxy                                                                             Me, H CH.sub.3 CH.sub.2 CH.sub.2 NHCO                                                         4-NH.sub.2                                                                            NMR, IR                                  134                                                                              6,7-methoxy                                                                             Me, H Me        4-CH.sub.3 CONH                                  135                                                                              6,7-methoxy                                                                             Et, H Bu        4-CH.sub.3 CONH                                  __________________________________________________________________________

In another embodiment, exemplary compounds of Formula II, Examples136-239, listed in Table 2, are provided, which can be prepared usingthe above methods using the appropriate starting materials and reagents.The synthesis of Example 185 is described below. ##STR5##

                                      TABLE 2                                     __________________________________________________________________________    Receptor Antagonists of Formula II.                                           EX. R.sup.1,R.sup.2,R.sup.3,R.sup.4                                                         R.sup.5                                                                           R.sup.16,R.sup.17                                                                   R.sup.18,R.sup.19                                                                      Anal.                                        __________________________________________________________________________    136 6,7-methylenedioxy                                                                      H   H,H   3-NH.sub.2                                                                             NMR,IR                                       137 6,7-methylenedioxy                                                                      Me  H,H   3-NH.sub.2                                            138 6,7-methylenedioxy                                                                      Et  H,H   3-NH.sub.2                                            139 6,7-methylenedioxy                                                                      Bu  H,H   3-NH.sub.2                                            140 6,7-methylenedioxy                                                                      H   H,H   3-NH.sub.2                                            141 6,7-methylenedioxy                                                                      Me  H,H   3-NH.sub.2                                            142 6,7-methylenedioxy                                                                      Et  H,H   3-NH.sub.2                                            143 6,7-methylenedioxy                                                                      Bu  H,H   3-NH.sub.2                                            144 6,7-methylenedioxy                                                                      H   5-Cl,H                                                                              3-NH.sub.2                                            145 6,7-methylenedioxy                                                                      Me  5-Cl,H                                                                              3-NH.sub.2                                            146 6,7-methylenedioxy                                                                      Et  5-Cl,H                                                                              3-NH.sub.2                                            147 6,7-methylenedioxy                                                                      Bu  5-Cl,H                                                                              3-NH.sub.2                                            148 6,7-methylenedioxy                                                                      H   5-MeO,H                                                                             3-NH.sub.2                                            149 6,7-methylenedioxy                                                                      Me  5-MeO,H                                                                             3-NH.sub.2                                            150 6,7-methylenedioxy                                                                      Lt  5-MeO,H                                                                             3-NH.sub.2                                            151 6,7-methylenedioxy                                                                      Bu  5-MeO,H                                                                             3-NH.sub.2                                            152 7-methoxy H   H,H   3-NH.sub.2                                            153 7-methoxy Me  H,H   3-NH.sub.2                                            154 7-methoxy Et  H,H   3-NH.sub.2                                            155 7-methoxy Bu  H,H   3-NH.sub.2                                            156 7-methoxy H   H,H   3-NH.sub.2                                            157 7-methoxy Me  H,H   3-NH.sub.2                                            158 7-methoxy Et  H,H   3-NH.sub.2                                            159 7-methoxy Bu  H,H   3-NH.sub.2                                            160 7-methoxy H   5-Cl,H                                                                              3-NH.sub.2                                            161 7-methoxy Me  5-Cl,H                                                                              3-NH.sub.2                                            162 7-methoxy Et  5-Cl,H                                                                              3-NH.sub.2                                            163 7-methoxy Bu  5-Cl,H                                                                              3-NH.sub.2                                            164 7-methoxy H   5-MeO,H                                                                             3-NH.sub.2                                            165 7-methoxy Me  5-MeO,H                                                                             3-NH.sub.2                                            166 7-methoxy Et  5-MeO,H                                                                             3-NH.sub.2                                            167 7-methoxy Bu  5-Meo,H                                                                             3-NH.sub.2                                            168 7-methyl  H   H,H   3-NH.sub.2                                            169 7-methyl  Me  H,H   3-NH.sub.2                                            170 7-methyl  Et  H,H   3-NH.sub.2                                            171 7-methyl  Bu  H,H   3-NH.sub.2                                            172 7-methyl  H   H,H   3-NH.sub.2                                            173 7-methyl  Me  H,H   3-NH.sub.2                                            174 7-methyl  Et  H,H   3-NH.sub.2                                            175 7-methyl  Bu  H,H   3-NH.sub.2                                            176 7-methyl  H   5-Cl,H                                                                              3-NH.sub.2                                            177 7-methyl  Me  5-Cl,H                                                                              3-NH.sub.2                                            178 7-methyl  Et  5-Cl,H                                                                              3-NH.sub.2                                            179 7-methyl  Bu  5-Cl,H                                                                              3-NH.sub.2                                            170 7-methyl  H   5-MeO,H                                                                             3-NH.sub.2                                            181 7-methyl  Me  5-MeO,H                                                                             3-NH.sub.2                                            182 7-methyl  Et  5-MeO,H                                                                             3-NH                                                  183 7-methyl  Bu  5-MeO,H                                                                             3-NH.sub.2                                            184 6,7-methylenedioxy                                                                      H   H,H   4-NH.sub.2                                                                             NMR,IR                                       185 6,7-methylenedioxy                                                                      Me  H,H   4-NH.sub.2                                                                             NMR,IR                                       186 6,7-methylenedioxy                                                                      Et  H,H   4-NH.sub.2                                            187 6,7-methylenedioxy                                                                      Bu  H,H   4-NH.sub.2                                            188 6,7-methylenedioxy                                                                      H   H,H   4-NH.sub.2                                            189 6,7-methylenedioxy                                                                      Me  H,H   4-NH.sub.2                                            190 6,7-methylenedioxy                                                                      Et  H,H   4-NH.sub.2                                            191 6,7-methylenedioxy                                                                      Bu  H,H   4-NH.sub.2                                            192 6,7-methylenedioxy                                                                      H   5-Cl,H                                                                              4-NH.sub.2                                            193 6,7-methylenedioxy                                                                      Me  5-Cl,H                                                                              4-NH.sub.2                                            194 6,7-methylenedioxy                                                                      Et  5-Cl,H                                                                              4-NH.sub.2                                            195 6,7-methylenedioxy                                                                      Bu  5-Cl,H                                                                              4-NH.sub.2                                            196 6,7-methylenedioxy                                                                      H   5-MeO,H                                                                             4-NH.sub.2                                            197 6,7-methylenedioxy                                                                      Me  5-MeO,H                                                                             4-NH.sub.2                                            198 6,7-methylenedioxy                                                                      Et  5-MeO,H                                                                             4-NH.sub.2                                            199 6,7-methylenedioxy                                                                      Bu  5-MeO,H                                                                             4-NH.sub.2                                            200 7-methoxy H   H,H   4-NH.sub.2                                            201 7-methoxy Me  H,H   4-NH.sub.2                                            202 7-methoxy Et  H,H   4-NH.sub.2                                            203 7-methoxy Bu  H,H   4-NH.sub.2                                            204 7-methoxy H   H,H   4-NH.sub.2                                            205 7-methoxy Me  H,H   4-NH.sub.2                                            206 7-methoxy Et  H,H   4-NH.sub.2                                            207 7-methoxy Bu  H,H   4NH.sub.2                                             208 7-methoxy H   5-Cl,H                                                                              4-NH.sub.2                                            209 7-methoxy Me  H,H   4-NH.sub.2                                            200 7-methoxy Et  5-Cl,H                                                                              4-NH.sub.2                                            211 7-methoxy Bu  5-Cl,H                                                                              4-NH.sub.2                                            212 7-methoxy H   5-MeO,H                                                                             4-NH.sub.2                                            213 7-methoxy Me  5-MeO,H                                                                             4-NH.sub.2                                            214 7-methoxy Et  5-MeO,H                                                                             4-NH.sub.2                                            215 7-methoxy Bu  5-MeO,H                                                                             4-NH.sub.2                                            216 7-methyl  H   H,H   4-NH.sub.2                                            217 7-methyl  Me  H,H   4-NH.sub.2                                            218 7-methyl  Et  H,H   4-NH.sub.2                                            219 7-methyl  Bu  H,H   4-NH.sub.2                                            220 7-methyl  H   H,H   4-NH.sub.2                                            221 7-methyl  Me  H,H   4-NH.sub.2                                            222 7-methyl  Et  H,H   4-NH.sub.2                                            223 7-methyl  Bu  H,H   4-NH.sub.2                                            224 7-methyl  H   5-Cl,H                                                                              4-NH.sub.2                                            225 7-methyl  Me  5-Cl,H                                                                              4-NH.sub.2                                            226 7-methyl  Et  5-Cl,H                                                                              4-NH.sub.2                                            227 7-methyl  Bu  5-Cl,H                                                                              4-NH.sub.2                                            228 7-methyl  H   5-MeO,H                                                                             4-NH.sub.2                                            229 7-methyl  Me  5-MeO,H                                                                             4-NH.sub.2                                            230 7-methyl  Et  5-MeO,H                                                                             4-NH.sub.2                                            231 7-methyl  Bu  5-MeO,H                                                                             4-NH.sub.2                                            232 6,7-methylenedioxy                                                                      H   H,H   4-NHMe                                                233 6,7-methylenedioxy                                                                      Me  H,H   4-NHMe                                                234 6,7-methylenedioxy                                                                      Et  H,H   4-NHMe                                                235 6,7-methylenedioxy                                                                      Bu  H,H   4-NHMe                                                236 6,7-methylenedioxy                                                                      H   H,H   4-CH.sub.3 CONH                                                                        NMR,IR                                       237 6,7-methylenedioxy                                                                      Me  H,H   4-CH.sub.3 CONH                                                                        NMR,IR                                       238 6,7-methylenedioxy                                                                      Et  H,H   4-CH.sub.3 CONH                                       239 6,7-methylenedioxy                                                                      Bu  H,H   4-CH.sub.3 CONH                                       __________________________________________________________________________

IV. IN VITRO AND IN VIVO ASSAYS OF ACTIVITY AND THERAPEUTIC EFFICACY

In vivo and in vitro assays may be conducted to determine the activityof the compounds as antagonists of the non-NMDA receptors, i.e., theionotropic EAA receptors which bind AMPA or KA. In combination, in vitroand in vivo assays are predictive of the activity of these compounds fortreatment of patients. This is supported, for example, by numerousstudies in the literature illustrating that in vitro and in vivo studiesof NMDA receptor modulation by a test compound provide a good indicationof the compound's efficacy in treating disorders associated withexcessive activation of the NMDA receptor. See, e.g.: Meldrum, EpilepsyResearch, 12:189-196 (1992); Lipton and Rosenberg, New England Journalof Medicine, 330:613-622 (1994); and McBurney, Neurobiology of Aging,15:271-273 (1994).

Electrophysiology

The potency of Examples 1-5, 7, 11, 17 and 31 listed in Table 1, fordrug inhibition of the AMPA receptor was tested using the whole-cellpatch clamp technique on primary cultures of rat neocortex. The generalprocedure for stimulating AMPA-receptor mediated currents with KA andfor the measurement of current inhibition is based on that used byDonevan and Rogawski (Neuron, 10:51-59, 1993) for 2,3-benzodiazepines.

Standard extracellular bath solutions and intracellular pipettesolutions are used as described in detail by Hussy and coworkers (J.Physiol. (Lond.), 481.2:311-323,1994). The drug application system isdesigned to allow rapid switching between 7 different reservoirscontaining either control bath solution, kainic acid (50 μM), or kainicacid (50 μM) plus antagonist (10 μM). Each recording is begun with acontrol response to KA alone.

Following the establishment of a 2-3 sec duration steady baseline,bathing solution is switched to one containing KA plus antagonist for anadditional 2-3 sec period. Alternatively, 5 different doses of a singlecompound are tested for the determination of the antagonist IC₅₀. Theresults of the assay of Examples 1-5, 7, 11, 17 and 31 are listed belowin Table 3, which illustrates AMPA receptor inhibition in rat corticalneurons. The compounds tested all were useful as antagonists of non-NMDAEAA receptors. All of the compounds tested were found to have a %inhibition ≧20 at a dose of 10 μM. Compounds which have a percentinhibition of greater than or equal to about 20% at a dose of about 10μM are generally useful antagonists of the non-NMDA EAA receptors asdisclosed herein.

                  TABLE 3                                                         ______________________________________                                        Inhibition of AMPA Binding to Receptor.                                                      AMPA %                                                                        INHIBITION AMPA                                                EXAMPLE        (10 μM drug)                                                                          IC50 μM                                          ______________________________________                                        1              20         23                                                  2              55         7.2                                                 3              80         2.8                                                 4              45         --                                                  5              86         1.8                                                 7              70         5.4                                                 11             36         --                                                  17             20         --                                                  31             33         --                                                  ______________________________________                                    

Neurodegenerative Transient Global Forebrain Ischemia

The extent of protection by a test compound in a model of brain ischemiamay be assayed as described by Meldrum et al. (Brain Res., 571:115,1992), and references cited therein. Male Wistar rats (250-300 g) areanesthetized using halothane-oxygen-nitrogen mixture and both vertebralarteries are permanently occluded by electrocauterisation within thealar foraminae of the first cervical vertebra. At the same time, bothcommon carotid arteries are isolated and atraumatic clamps placed aroundeach one. One femoral vein is cannulated to enable the subsequent ivadministration of fluid. The following day cerebral ischemia is inducedin the unanaesthetised animal, by tightening the clamps around thecarotid arteries for 20 min. Carotid clamping results. Body temperatureis maintained at 37° C. by use of a rectal probe and hot plate. Sevendays after the ischemic insult rats are sacrificed and the brainsprocessed for light microscopy. Neuroprotection is assessed byexamination of the extent of damage in the cortex and hippocampus.Compounds may be selected which are active in this model.

Neurodegenerative Permanent Focal Ischemia

The extent of protection by a test compound in a model of brain ischemiamay be tested using a model described by Meldrum and Smith (Stroke,23:861, 1992), and references cited therein. Male Fisher F344 rats(210-310 g) are anesthetized with halothane-oxygen-nitrogen mixturereceive a small incision between the eye and ear, the mandibular musclesare retracted to expose the orbit and zygomatic arch. A small craniotomyis made to expose the base of the middle cerebral artery. Bipolarcoagulation is used to permanently occlude the artery at the base. Oneday after the ischemic insult rats are sacrificed and the brainsprocessed for light microscopic examination. Lesion volume is determinedby using Cavalarei's principle. Compounds may be selected which areactive in this model.

Maximum Electro Shock (MES) Seizure Test

The extent of protection by a test compound in a seizure model is testedas described by Rogawski et al. (Epilepsy Research, 15:179-184, 1993).Male NIH Swiss mice (25-30 g) are injected ip with the test drug. Themice are subjected to a 0.2 sec, 60 Hz, 50 mA electrical stimulusdelivered with corneal electrodes wetted with 0.9% saline at 15-30 minpost dosing. Animals failing to show tonic hind limb extension arescored as protected. Compounds may be selected which are active in thismodel.

The results of this assay using the compounds, Examples 2, 3, and 133are shown below in Table 4.

                  TABLE 4                                                         ______________________________________                                        MES Test Results                                                                                             Score                                                                         (protected/                                              Dose         Time    no.                                            Example   (mg/kg)      (hours) tested)                                        ______________________________________                                        2         30           0.5     3/3                                            3         31           0.5     5/8                                            133       30           0.5     1/3                                            ______________________________________                                    

Subcutaneous Metrazol (scMET) Seizure Test

This test is to determine the extent of protection by a test compound ina seizure model. The method used is that of Chen et at. (Proc. Soc. Exp.Biol. Med., 87:334, 1954). Mice are randomly assigned to vehicle ortreatment groups of 3-10 animals per group and then dosed accordingly.Metrazol (pentylenetetrazol) 90 mg/kg is administered subcutaneously(sc) at different time points (0.25, 0.5, 1, 2, 4 hr) after thetreatment or control groups. The mice individually housed in clear runsand observed for the presence or absence of clonic seizure activity (>5s duration) for 30 min after metrazol dosing. A compound is consideredactive if no seizure is observed. Data is analyzed using a quantalmeasure (protection/number tested).

The results of this assay using the compound, Example 133, is shownbelow in Table 5.

                  TABLE 5                                                         ______________________________________                                        scMET Test Results                                                                                           Score                                                   Dose                  (protect./no.                                  Example  (mg/kg)      Time (hr)                                                                              tested)                                        ______________________________________                                        133      30           0.5      1/5                                            ______________________________________                                    

The compounds can be administered parenterally, i.e., subcutaneously,intramuscularly, or intravenously and, alternatively, administeredorally, in a dose range of between about 0.01 and 100 mg/kg body weight.

The active ingredient can be administered parenterally in sterile liquiddosage forms. In general, water, a suitable oil, saline, aqueousdextrose, and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble form of the active ingredient, suitable stabilizingagents, and, if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid either alone orcombined are suitable stabilizing agents. Also solutions can containpreservatives, such as benzalkonium chloride, methyl- or propylparaben,and chlorobutanol.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. Gelatin capsules contain the activeingredient and powdered carriers, such as lactose, starch, cellulosederivatives, magnesium stearate, stearic acid, and the like. Similardiluents can be used to make compressed tablets. Both tablets andcapsules can be manufactured as sustained release products to providefor continuous release of medication over a period of hours. The activeingredients also may be provided in a particle for sustained or pulseddelivery such as a liposome or microcapsule. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, a standard reference text in thisfield.

Optionally, the compounds either alone or in combination with a carriermay be administered by implantation or by application to a mucosalsurface, for example, the nasal-pharyngeal region and/or lungs using anaerosol or may be administered to a skin surface via a topical carriersuch as a cream or lotion.

The compounds of this invention and their preparation can be understoodfurther by the following non-limiting examples which describe thesynthesis of exemplary compounds of Formula I (see Table D. In theseexamples, unless otherwise indicated, all temperatures are in degreesCelsius and parts and percentages are by weight.

EXAMPLE 1 Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-(N"-methylcarbamoyl)-6,7-methylendioxyphthalazine

Part A: Preparation of 1-Bromo-3,4-methylendioxy-benzaldehyde

Piperanal (30 g 0.20 mole) was dissolved in acetic acid (200 mL andtreated with a solution of bromine (80 g, 0.50 mole) in acetic acid (100mL). The solution stirred at ambient temperature for 24 h and then water(300 mL) was added. After stirring for 15 minutes the solid precipitatewas collected by filtration, washed with water and recrystallized from10% aqueous methanol (450 mL). The resultant solid weighed 23 g (50%).Mp 123°-5° C. IR (PTFE Film); 1672 cm⁻¹, 1610, 1487, 1112, 923, 887.

Part B: Preparation of5-Bromo-6-(1,3-dioxolanyl-2-yl)-2,3-methylenedioxybenzene

A mixture of 5-Bromo-3,4-methylendioxy-benzaldehyde (16 g, 70 mmole),ethylene glycol (8.7 g, 0.14 mole), toluensulfonic acid monohydrate(0.50 g) and toluene (450 mL) were stirred rapidly and heated to refluxwhile water was removed with a Dean-Stark apparatus. After one hour themixture was cooled to 20° C., washed with water (200 mL) and aqueoussaturated sodium bicarbonate (100 mL), dried (MgSO₄) and evaporated invacuo to leave a yellow oil. The oil was crystallized from hexanes-EtOActo afford a beige solid (8.9 g, 47%). The filtrate was concentrated andchromatographed on silica gel eluting with 20% EtOAc/hexanes to 25%EtOAc/hexanes. The isolated oil was crystallized from hexanes-EtOAc toleave an additional 4.8 g. Total yield=13.7 g (72%). Mp 69°-71° C. 200MHz ¹ H-NMR (CDCl₃); δ7.10 (s, 1H), 7.00 (s, 1H), 6.08 (s, 1H, ArCH),6.00 (s, 2H), 4.12 (m, 4H, OCH₂ CH₂ O): IR (PTFE film); 1503 cm⁻¹, 1471,1241, 1036.

Part C: Preparation of N'-Methoxyl-N'-methyl-4-nitrobenzenecarboxamide

A mixture of p-nitrobenzoyl chloride (30 g, 0.16 mole),N,O,-dimethylhydroxylamine hydrochloride (17 g, 0.18 mole) and methylenechloride (500 mL) were stirred and cooled in an ice bath. Pyridine (28g, 0.36 mole) was added dropwise over 5 minutes and the mixture stirredan additional 2 hours. The solvents were evaporated in vacuo, theresidue was treated with EtOAc (300 mL) and 1N HCl (100 mL) andseparated. The aqueous layer was washed with EtOAc (100 mL), thecombined organic layers were dried (MgSO₄) and evaporated in vacuo toleave a yellow oil that crystallized upon treatment with ether-hexanes.The light yellow solid was collected by filtration, washed(ether-hexanes) and air dried to afford 24 g (71%) of the amide. Mp71°-74° C.

Part D: Preparation of N'-Methoxyl-N'-methyl-4-aminobenzenecarboxamide

N'-Methoxyl-N'-methyl-4-nitrobenzenecarboxamide (22 g, 0.10 mole), 10%palladium on carbon (1.0 g) and methanol (500 mL) were agitated on aParr shaker under 45 p.s.i. initial pressure. After 30 minutes no morehydrogen uptake was observed. The catalyst was filtered, washed(methanol) and the filtrate was evaporated in vacuo to afford a tansolid. The solid was chromatographed on silica gel eluting with agradient of 33% hexanes/EtOAc to 25% hexanes/EtOAc. The amine wasobtained as a tan solid (19 g, 100%). Mp 91°-94° C. 200 MHz ¹ H-NMR(CDCl₃); δ7.63 (d, 2H, J=8.4 Hz, H²), 6.66 (d, 2H, J=8.4 Hz, H₃), 3.95(bs, 2H, NH₂), 3.60 (s, 3H, OCH₃), 3.34 (s, 3H, NCH₃).

Part E: Preparation of4-N'-(2',2'-Diphenylimino)-N-methoxyl-N-methylcarboxamide

A mixture of N'-Methoxyl-N'-methyl-4-aminobenzenecarboxamide (18 g, 0.10mole), benzophenone imine (19 g, 0.11 mole), boron trifluoride etherate(5 mL) and toluene (400 mL) was stirred and heated to reflux under anitrogen atmosphere for 4 hours. The mixture was cooled to ambienttemperature and washed with saturated aqueous sodium bicarbonate (100mL), water (100 mL) and brine (100 mL). The dried (MgSO₄) organic layerwas evaporated in vacuo to leave a yellow solid that recrystallized fromhexanes-EtOAc (23 g, 67%). The filtrate was condensed andchromatographed on silica gel eluting with a gradient of 25%hexane/EtOAc to 33% hexane/EtOAc to 50% hexane/EtOAc. Another 4.7 g(14%) of product was isolated. Total yield=27.7 g (81%). Mp 123°-6° C.200 MHz ¹ H-NMR (CDCl₃); δ7.53 (d, 2H, J=7.8 Hz, H²), 7.40 (m, 10H,ArH), 6.72 (d, 2H, J=7.8 Hz, H³), 3.50 (s, 3H, OCH₃), 3.30 (s, 3H,NCH₃).

Part F: Preparation of 2-(1,3-Dioxolan-2-yl)4-diphenylimino-4,5-methylenedioxybenzophenone

An oven dried, 3-necked, 250 mL flask was purged with nitrogen, chargedwith 5-bromo-6-(1,3-dioxolanyl-2-yl)-2,3-methylenedioxybenzene (7.5 g,27 mmole) and THF (80 mL, freshly distilled from sodium benzophenoneketyl). The solution was cooled to -78° C. and n-butyl lithium (12 mL ofa 2.5M solution in hexanes, 30 mmole) was added dropwise over 5 minutes.Two minutes after the addition of butyl lithium was completed thesolution was added via cannula to a solution of4-N'-(2',2'-Diphenylimino)-N-methoxyl-N-methylcarboxamide (9.5 g, 27mmole) and distilled THF (80 mL) in an oven dried, nitrogen purged,3-necked, 500 mL flask at -78° C. After 15 minutes the dry-ice bath wasremoved and the mixture stirred 14 hours at 20° C. and then was pouredinto a mixture of EtOAc (500 mL) and water (200 mL). The layers wereseparated, the aqueous layer was extracted with EtOAc (100 mL), combinedwith the earlier organic layer, dried (MgSO₄) and evaporated to leave ayellow solid. Recrystallization from EtOAc provided bright yellowneedles (8.2 g, 64%). Mp 187°-9° C. 200 MHz ¹ H-NMR (CDCl₃); δ7.68 (d,2H, J=8.4 Hz), 7.40 (m, 10H, ArH), 6.76 (s, 1H), 6.75 (d, 2H, J=8.4 Hz),6.06 (s, 2H, OCH₂ O), 5.81 (s, 1H, OCHO), 3.85 (m, 4H, OCH₂ CH₂₀): FABLRMS (mBNA); 478 (M+1).

Part G: Preparation of 1-(4-Aminophenyl)-6,7-methylendioxyphthalazine

2-(1,3-Dioxolan-2-yl)-4'-diphenylimino-4,5-methylenedioxy-benzo phenone(5.7 g, 12 mmole) and hydrazine dihydrochloride (1.4 g, 13 mmole) weredissolved in methanol (250 mL) and water (25 mL). Hydrazine (0.42 g, 13mmole) was added and the mixture stirred for 16 hours at 20° C. Thesolvents were evaporated in vacuo to one quarter the original volume,EtOAc (300 mL), water (300 mL) and 1N HCl (10 mL) were added. Theorganic layer was further washed with water and the combined aqueouslayers were neutralized with 1N NaOH. The precipitate was extracted withdichloromethane (4×500 mL), dried (MgSO₄) and evaporated to leave a tansolid. The crude product was chromatographed on silica gel eluting with10% methanol/EtOAc to afford the aminophenylphthalazine as a tan solid(2.2 g, 69%). Mp 221°-223° C. (dec.). 200 MHz ¹ H-NMR (CDCl₃); δ9.28 (s,1H), 7.58 (d, 2H, J=8.6 Hz), 7.41 (s, 1H), 7.21 (s, 1H), 6.84 (d, 2H,J=8.6 Hz), 6.17 (s, 2H, 0CHO), 3.90 (bs, 2H, NH₂): FAB LRMS (mNBA); 266(M+1).

Part H: Preparation of1-(4-Acetylaminophenyl)-6,7-methylendioxyphthalazine

1-(4-Aminophenyl)-6,7-methylendioxyphthalazine (3.0 g, 11 mmole) andacetic anhydride (50 mL) were stirred at ambient temperature for 3 h.The dark green mixture was cooled in an ice bath and treated with 1N HCl(200 mL). After 30 min the mixture was filtered through celite,neutralized with solid sodium carbonate and the resulting precipitatewas filtered, washed with water (3×50 mL) and vacuum dried to leave atan solid (3.1 g, 92%). A 0.17 g sample was recrystallized frommethanol-water to leave a light yellow solid. TLC is homogeneous (20%methanol/EtOAc). Mp 268°-270° C. (dec.). 200 MHz ¹ H-NMR (DMSO-d₆);δ10.30 (brs, 1H, NH), 9.53 (s, 1H), 7.93 (d, 2H, J=7.0 Hz), 7.76 (d, 2H,J=7.0 Hz), 7.75 (s, 1H), 7.37 (s, 1H), 6.43 (s, 2H, 0CHO), 2.24 (s, 3H,COCH₃): CI (CH₄) LRMS; 308 (M+1).

Part I: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylenedioxyphthalazine

An oven dried, 3-necked, 250 mL flask was purged with nitrogen andcharged with 1-(4-acetylaminophenyl)-6,7-methylendioxyphthalazine (1.0g, 3.3 mmole), distilled THF (30 mL) and TMEDA (10 mL). The suspensionwas cooled in an ice bath and treated dropwise over five minutes with anether solution of methyl lithium (9.3 mL of a 1.4M solution, 13 mmole).The dark brown mixture was stirred for 1 h, treated cautiously withwater (5 mL) then dichloromethane (120 mL). The contents of the flaskwere transferred to a separatory funnel, water (100 mL) was added andthe layers were separated. The aqueous phase was further extracted withdichloromethane (50 mL), the extracts combined, washed with brine (100mL), dried (MgSO₄) and evaporated in vacuo. The tan foamy residue wasdissolved in methanol (20 mL), silica gel was added and the solvent wasevaporated to complete dryness. The crude product was chromatographed onsilica gel eluted with EtOAc to afford the addition product a light tancrystalline solid (0.53 g, 50%). Mp 236°-239° C. 200 MHz ¹ H-NMR(CDCl₃); δ7.59 (s, 4H), 7.26 (brs, 1H, NHCOCH₃), 6.75 (s, 1H), 6.73 (s,1H), 6.00 (s, 2H, 0CHO), 5.88 (brs, 1H), 4.31 (q, 1H, J=6.4 Hz,--CHCH₃), 2.60 (s, 3H, COCH₃), 1.48 (d, 3H, J=6.4 Hz, CHCH₃).

Part J: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-1-methyl-2-(N"-methylcarbamoyl)-6,7-methylendioxyphthalazine

To a suspension of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl1-6,7-methylendioxyphthalazine (0.27 g, 1.2 mmole) in dichloromethane (20 mL) was addeddimethylaminopyridine (DMAP, 20 mg) and a large excess ofmethylisocyanate (1.0 mL). The mixture stirred at ambient temperaturefor 24 h. during which time the phthalazine dissolved completely. Moremethylisocyanate (1 mL) was added, the solution stirred another 24 hoursand the mixture was blown to near dryness with a stream of nitrogen. Theresidue was chromatographed on silica gel and eluted with 5%methanol/dichloromethane. The desired product was obtained as a lightyellow powder (0.27 g, 81%). 200 MHz ¹ H-NMR (DMSO-d₆); δ7.83 (s, 4H'),7.31 (q, 1H, J=5.7 Hz, NHCH₃), 7.25 (s, 1H), 6.85 (s, 1H), 6.23 (s, 1H,0CHO), 6.21 (s, 1H, 0CHO), 5.90 (s, 1H, NHCOCH₃), 5.70 (q, 1H, J=7.1 Hz,CHCH₃), 2.88 (d, 3H, J=5.7 Hz, NHCH₃), 2.23 (s, 3H, COCH₃), 1.22 (d, 3H,J=7.1 Hz, CHCH₃): CI (CH₄) LRMS; 381 (M+1).

Part K: Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-(N"-methylcarbamoyl)-6,7-methylendioxyphthalazine

A solution of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-2-(N"-methylcarbamoyl)-6,7-methylendioxyphthalazine(186 mg, 0.49 mmole), 1N NaOH (3 mL) and methanol (7 mL) was heated toreflux for 72 hours, cooled to ambient temperature and diluted withwater (10 mL) and dichloromethane (20 mL). The aqueous phase was furtherextracted with dichloromethane (2×10 mL), combined with the earlierorganic phase, dried (MgSO₄) and evaporated in vacuo to leave a yellowfoamy residue. Chromatography on silica gel (25% hexanes/EtOAc) providedas a light yellow foamy solid (115 mg, 69%). 200 MHz ¹ H-NMR (DMSO-d₆);δ7.55 (d, 2H, J=8.8 Hz), 7.20 (s, 1H), 7.18 (q, 1H, J=4.4 Hz, NHCH₃),6.87 (s, 1H), 6.76 (d, 2H, J=8.8 Hz), 6.21 (s, 1H, OCH₂ O), 6.18 (s,1H), 5.64 (q, 1H, J=7.3 Hz, CHCH₃), 5.56 (bs, 2H, NH₂), 2.86 (d, 3H,J=4.4 Hz, NHCH₃), 1.17 (d, 3H, J=7.3 Hz, CHCH₃): CI (CH₄) LRMS; 339(M+1).

EXAMPLE 2 Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-(N-ethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-2-(N-ethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

A suspension of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylendioxyphthalazine(0.10 g, 0.31 mmole) in dichloromethane was treated with ethylisocyanate(1 mL). After stirring for 2 hours more ethylisocyanate (1 mL) was addedand the mixture stirred an additional 14 hours Another portion ofethylisocyanate (1 mL) was added and the solution stirred another 6 h. Astream of nitrogen was blown through the reaction mixture until dryness.The residue was chromatographed on silica gel eluted with a gradient of75% EtOAc/hexanes to 100% EtOAc. The product was obtained as a tan foamyresidue (106 mg, 87%). 200 MHz ¹ H NMR (CDCl₃); δ7.60 (q, 4H, J=10.0 Hz,ArH), 7.32 (s, 1H, NHCOCH₃), 6.73 (s, 1H, ArH), 6.70 (s, 1H, ArH), 6.51(t, 1H, J=5.0 Hz, CONHCH₂), 5.98 (s, 2H, OCH₂ O), 5.68 (q, 1H, J=6.7 Hz,CHCH₃), 4.12 and 3.38 (m, 2H, NHCH₂ CH₃), 2.23 (s, 3H, COCH₃), 1.34 and1.20 (t, J=7.0 Hz and J=8.0 Hz, CH₂ CHH₃), 1.23 (d, 3H, J=6.7 Hz,CHCH₃).

Part B: Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-(N-ethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

To a solution of the above dihydrophthalazine (0.10 g, 0.26 mmole) inmethanol (4 mL) was added 1N sodium hydroxide (2 mL). The mixture wasstirred and heated to reflux for 72 hours. After cooling to ambienttemperature the solution was diluted with EtOAc (25 mL), washed withwater (50 mL), dried (MgSO₄) and evaporated in vacuo. The residue waschromatographed on silica gel eluted with a gradient of 50%EtOAc/hexanes to 67% EtOAc/hexanes to afford the product as a lightyellow foamy solid (77 mg, 84%). 200 MHz ¹ H NMR (CDCl₃); δ7.45 (d, 2H,J=9.4 Hz, ArH_(2')), 6.84 (s, 1H, ArH), 6.79 (d, 2H, J=9.4 Hz,ArH_(3')), 6.73 (s, 1H, ArH), 6.57 (t, 1H, J=4.7 Hz, CONH), 6.02 (s, 2H,OCH₂ O), 5.70 (q, 1H, J=7.8 Hz, CHCH₃), 3.90 (bs, 2H, NH₂), 3.41 (m, 2H,NHCH₂), 1.27 (d, 3H, J=7.8 Hz, CHCH₃), 1.20 (t, 3H, J=7.0 Hz, CH₂ CH₃):CI LRMS (CH₄); 353 (M+1).

EXAMPLE 3 Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylendioxyphthalazine

A mixture of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylendioxyphthalazine(0.10 g, 0.31 mmole) and dichloromethane (5 mL) was stirred and treatedwith propylisocyanate (0.5 mL). After 5 hours more propylisocyanate (0.5mL) was added and the mixture stirred for 48 h. The solvents were blowndry with a stream of nitrogen and the residue was chromatographed onsilica gel eluted with a gradient of 33% hexanes/EtOAc to 25%hexanes/EtOAc. The resultant product was a light yellow foamy solid (108mg, 86%). 200 MHz ¹ H NMR (CDCl₃); δ7.63 (ABq, 4H, J=9.4 Hz, ArH'), 7.40(bs, 1H, ArNH), 6.77 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.62 (t, 1H, J=8.5Hz, NHCH₂), 6.02 (s, 2H, OCH₂₀), 5.71 (q, 1H, J=10.9 Hz, CHCH₃), 3.33(dt, 1H, J=8.5 Hz, J=7.8 Hz, NHCHCH₂), 2.18 (s, 3H, COCH₃), 1.61 (q, 2H,J=7.8 Hz, CH₂ CH₂ CH₃), 1.27 (d, 3H, J=10.9 Hz, CHCH₃), 0.98 (t, 3H,J=7.8 Hz, CH₂ CH₃).

Part B: Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylendioxyphthalazine

A solution of the above dihydrophthalazine (0.10 g, 0.25 mmole) in 1Nsodium hydroxide (4 mL) and methanol (8 mL) was stirred and heated toreflux for 72 hours. The solution was cooled to ambient temperature,diluted with EtOAc (30 mL) and washed with water (30 mL). The aqueouslayer was extracted with EtOAc (25 mL) and the combined organic layerswere dried (MgSO₄) and evaporated in vacuo. The crude product waschromatographed on silica gel eluted with 50% hexanes/EtOAc to affordthe pure product as a light yellow foamy solid (75 mg, 82%). 200 MHz ¹ HNMR (CDCl₃); δ7.41 (d, 2H, J=6.5 Hz, ArH), 6.81 (s, 1H, ArH), 6.77 (d,2H, J=6.5 Hz, ArH), 6.71 (s, 1H, ArH), 6.00 (s, 2H, OCH₂ O), 5.67 (q,1H, J=6.7 Hz, CHCH₃), 3.85 (brs, 2H, NH₂), 3.30 (dt, 2H, J=8.3 Hz, J=6.2Hz, NHCH₂ CH₂), 1.58 (m, 2H, CH₂ CH₂ CH₃), 1.24 (d, 3H, J=6.7 Hz,CHCH₃), 0.95 (t, 3H, J=7.5 Hz, CH₂ CH₃).

EXAMPLE 4 Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-isopropylcarbamoyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-Acetylaminophenyl)-1,3-dihydro-2-methyl-3-isopropylcarbamoyl-6,7-methylendioxyphthalazine

A mixture of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylendioxyphthalazine(0.10 g, 0.31 mmole) and dichloromethane (5 mL) were stirred and treatedwith isopropylisocyanate (0.5 mL). The mixture stirred for 5 hours andwas treated again with isopropylisocyanate (0.5 mL). The mixture stirredanother 14 hours at which point it was treated again withisopropylisocyanate (0.5 mL). After another 5 hours of stirring thesolution was blown dry with a stream of nitrogen and the residue waschromatographed on silica gel (33% hexanes/EtOAc). The resultant productwas a light yellow foamy solid (103 mg, 82%). 200 MHz ¹ H NMR (CDCl₃);δ7.63 (ABq, 4H, J=12.5 Hz, ArH), 7.47 (brs, 1H, ArNH), 6.77 (s, 1H,ArH), 6.72 (s, 1H, ArH), 6.40 (d, 1H, J=10.0 Hz, NHCH), 6.01 (s, 2H,OCH₂ O), 5.71 (q, 1H, J=9.2 Hz, CHCH₃), 4.07 and 3.90 (m, 1H, NHCH),2.27 (s, 3H, COCH₃), 1.25 (d, 3H, J=9.2 Hz, CHCH₃), 1.23 and 1.17 (m,6H, J=9.4 Hz, CH(CH₃)₂).

Part B: Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-isopropylcarbamoyl-6,7-methylendioxyphthalazine

A solution of the dihydrophthalazine Pan A in 1N sodium hydroxide (4 mL)and methanol (8 mL) was stirred and heated to reflux for 72 hours. Themixture was cooled to ambient temperature, diluted with EtOAc (30 mL)and washed with water (30 mL). The aqueous layer was extracted withEtOAc (20 mL) and the combined organic layers were dried (MgSO₄) andevaporated. The residue was chromatographed on silica gel eluted with50% hexanes/EtOAc to leave the product as a light yellow solid (75 mg,82%). 200 MHz ¹ H NMR (CDCl₃); δ7.42 (d, 2H, J=6.5 Hz, ArH₂ '), 6.80 (s,1H, ArH), 6.77 (d, 2H, J=6.5 Hz, ArH), 6.71 (s, 1H, ArH), 6.39 (d, 1H,J=11.0 Hz, NHCH), 5.99 (s, 2H, OCH₂ O), 5.67 (q, 1H, J=6.2 Hz, CHCH₃),4.10 (m, 1H, CH(CH₃)₂), 3.89 (brs, 2H, NH₂), 1.24 (d, 3H, J=6.2 Hz,CHCH₃), 1.23 (d, 6H, J=6.6 Hz, CH(CH₃)₂): FTIR (PTFE film); 3344 cm⁻¹,2923, 2851, 1662, 1610, 1503, 1390, 1364, 1072, 1036.

EXAMPLE 11 Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-acetylaminophenyl)-1,2-dihydro-1-ethyl-6,7-methylendioxyphthalazine

An oven dried, 3-necked, 50 mL flask was purged with nitrogen andcharged with the 1-(4-aminophenyl)-6,7-methylendioxyphthalazine (0.20 g,0.65 mmole) and THF (distilled from sodium benzophenone ketyl). Themixture was cooled in an ice bath and treated with ethyl magnesiumbromide in ether (0.54 mL of a 3.0M solution, 1.6 mmole). The ice bathwas removed and the mixture stirred for 14 h. It was recooled in an icebath, treated with 1N HCl (25 mL) and dichloromethane (20 mL). Theaqueous layer was separated and neutralized with solid sodium carbonate(pH=12). The product was extracted with dichloromethane (3×25 mL). Allorganic phases were combined, dried (MgSO₄) and evaporated. The residuewas chromatographed on silica gel eluted with EtOAc to afford theproduct as a light yellow foamy solid (68 mg, 31%). 200 MHz ¹ H NMR(CDCl₃); δ7.57 (s, 4H, ArH), 7.23 (bs, 1H, ArNH), 6.75 (s, 1H, ArH),6.68 (s, 1H, ArH), 5.59 (s, 2H, OCH₂ O), 4.02 (t, 1H, J=6.9 Hz, CHCH₂),2.23 (s, 3H, COCH₃), 1.75 (m, 2H, CHCH₂ CH₃), 1.02 (t, 3H, J=7.6 Hz, CH₂CH₃).

Part B: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine

A solution of4-(4-acetylaminophenyl)-1,2-dihydro-1-ethyl-6,7-methylendioxyphthalazine(60 mg, 0.18 mmole) and THF (6 mL) were stirred and treated withmethylisocyanate (0.25 mL). The mixture was heated to reflux for 5 hoursand more methylisocyanate (0.25 mL) was added. Reflux continued foranother 14 hours and the mixture was then blown dry with a stream ofnitrogen. The residue was chromatographed on silica gel with 5%methanol/dichloromethane to leave the product as a light yellow foamysolid (52 mg, 73%). 200 MHz ¹ H NMR (CDCl₃); δ7.59 (q, 4H, J=5.1 Hz,ArH), 7.28 (bs, 1H, ArNH), 6.74 (s, 1H, ArH), 6.69 (s, 1H, ArH), 6.48(q, 1H, J=4.8 Hz, NHCH₃), 5.99 (d, 2H, J=2.2 Hz, OCH₂ O), 5.50 (t, 1H,J=6.2 Hz, CHCH₂), 2.93 and 2.86 (d pair, 3H, J=5.0 Hz and J=4.6 Hz,NHCH₃), 2.23 and 2.17 (s pair, 3H, COCH₃), 1.65 (m, 2H, CHCH₂ CH₃), 0.87(t, 3H, J=8.3 Hz, CH₂ CH₃).

Part C: Preparation of4-(4-Aminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine

A solution of4-(4-acetylaminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine(45 mg, 0.11 mmole) in 1N sodium hydroxide (4 mL) and methanol (6 mL)was heated to reflux for 72 hours. The mixture was cooled to ambienttemperature, diluted with EtOAc (30 mL), washed with water (25 mL),dried (MgSO₄) and evaporated in vacuo. The residue was chromatographedon silica gel with 25% hexanes/EtOAc to afford the product as a lightyellow foamy solid (35 mg, 90%). 200 MHz ¹ H NMR (CDCl₃); δ7.42 (d, 2H,J=8.1 Hz, ArH), 6.82 (s, 1H, ArH), 6.76 (d, 2H, J=8.1 Hz, ArH), 6.70 (s,1H, ArH), 6.50 (brq, 1H, J=5.4 Hz, NHCH₃), 5.59 (d, 2H, J=2.7 Hz, OCH₂O), 5.48 (t, 1H, J=6.8 Hz, CHCH₂), 2.93 (d, 3H, J=5.4 Hz, NHCH₃), 1.64(m, 2H, CHCH₂ CH₃), 0.87 (t, 3H, J=8.1 Hz, CH₂ CH₃).

EXAMPLE 23 Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-methoxycarbonyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-2-methoxycarbonyl-1-methyl-6,7-methylendioxyphthalazine

To a suspension of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylendioxyphthalazine(0.10g, 0.31 mmole) in THF (5 mL, freshly distilled from sodiumbenzophenone ketyl) and triethylamine (63 mg, 0.62 mmole, 86 mL) wasadded methylchloroformate (1 mL) over 1 minute with rapid stirring.After 2 hours more methylchloroformate was added (1 mL) and the mixturewas allowed to stir an additional hour. The solvents were evaporated invacuo and the residue was diluted with water (15 mL) and EtOAc (25 mL).The organic phase was separated, dried (MgSO₄) and evaporated. Theresidue was chromatographed on silica gel eluted with a gradient of 80%EtOAc/hexanes to 100% EtOAc. The product was obtained as a light yellowfoamy solid (125 mg, 98%). 200 MHz ¹ H NMR (CDCl₃); δ7.63 (s, 4H, ArH),7.38 (bs, 1H, NH), 6.77 (s, 1H, ArH), 6.70 (s, 1H, ArH), 6.00 (s, 2H,OCH₂ O), 5.52 (q, 1H, J=6.2 Hz, CHCH₃), 3.90 (s, 3H, OCH₃), 2.21 (s, 3H,COCH₃), 1.31 (d, 3H, J=6.2 Hz, CHCH₃).

Part B: Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-methoxycarbonyl-1-methyl-6,7-methylendioxyphthalazine

To a solution of the above dihydrophthalazine (83 mg, 0.22 mmole),4-dimethyl-aminopyridine (27 mg, 0.22 mmole), triethylamine (22 mg, 0.22mmole) and dichloromethane (4 mL) was added t-butyloxycarbonyl anhydride(95 mg, 0.44 mmole). The mixture was stirred for 6 hours, diluted withdichloromethane (25 mL), washed with 10% citric acid, dried (MgSO₄) andevaporated in vacuo. The residue was dissolved in THF (5 mL) and water(5 mL), treated with lithium hydroxide monohydrate and stirred for 2hours. The solution was diluted with brine (15 mL) and dichloromethane(40 mL), the aqueous layer was washed with dichloromethane, the organiclayers were combined dried (MgSO₄) and evaporated in vacuo. The residuewas treated with dichloromethane (4 mL) and TFA (4 mL), stirred for 30minutes, evaporated, treated with toluene, evaporated and the residuewas dissolved in 1N sodium hydroxide (10 mL) and EtOAc (10 mL). Theorganic layer was separated, dried (MgSO₄) and evaporated. The residuewas chromatographed on silica gel eluted with a gradient of 50%EtOAc/hexanes to 75% EtOAc/hexanes. The product was obtained as a lightyellow foamy solid (37 mg, 64%). 200 MHz ¹ H NMR (CDCl₃); δ7.47 (d, 2H,J=8.3 Hz, ArH), 6.83 (s, 1H, ArH), 6.73 (d, 2H, J=8.3 Hz, ArH), 6.69 (s,1H, ArH), 5.59 (s, 2H, OCH₂ O), 5.50 (q, 1H, J=6.7 Hz, CHCH₃), 3.88 (s,3H, OCH₃), 3.84 (bs, 2H, NH2), 1.30 (d, 3H, J=6.7 Hz, CHCH₃): CI LRMS(CH₄); 340 (M+1).

EXAMPLE 31 Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

Part A: Preparation of4-(4-Acetylaminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

A solution of4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylendioxyphthalazine(0.10 g, 0.31 mmole), 4-dimethylaminopyridine (20 mg) anddiisopropylethylamine (0.50 mL) in THF was treated withN,N-dimethylcarbamoyl chloride (0.50 mL). The mixture was heated toreflux for 14 hours, cooled to ambient temperature, diluted withdichloromethane (20 mL), washed with 0.2N HCl (20 mL), dried (MgSO₄) andevaporated in vacuo to leave a green solid that was chromatographed onsilica gel with EtOAc. The pure product was a beige solid (107 mg, 88%).200 MHz ¹ H NMR (CDCl₃); δ7.62 (s, 4H, ArH), 6.77 (s, 1H, ArH), 6.70 (s,1H, ArH), 6.00 (d, 2H, J=2.1 Hz, OCH₂ O), 5.27 (q, 1H, J=6.2 Hz, CHCH₃),3.06 (s, 6H, N(CH₃)₂), 2.23 (s, 3H, COCH₃), 1.32 (d, 3H, J=6.2 Hz,CHCH₃).

Part B: Preparation of4-(4-Aminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine

A solution of4-(4-acetylaminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine(97 mg, 0.25 mmole) in 1N sodium hydroxide (3 mL) and methanol (7 mL)was heated to reflux for 72 hours, cooled to ambient temperature,diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer waswashed with EtOAc and the combined organic layers were dried (MgSO₄) andevaporated. The residue was chromatographed on silica gel with 25%hexanes/EtOAc to leave a light yellow foamy solid (63 mg, 72%). 200 MHz¹ H NMR (CDCl₃); δ7.45 (d, 2H, J=8.6 Hz, ArH₂ '), 6.84 (s, 1H, ArH),6.76 (d, 2H, J=8.6 Hz, ArH), 6.71 (s, 1H, ArH), 6.01 (d, 2H, J=2.9 Hz,OCH₂ O), 5.25 (q, 1H, J=7.1 Hz, CHCH₃), 3.95 (brs, 2H, NH₂), 3.07 (s,6H, N(CH₃)₂), 1.33 (d, 3H, J=7.1 Hz, CHCH₃): FTIR (PTFE film); 3456cm⁻¹, 3343, 3220, 1631, 1605, 1482, 1379, 1251, 1036.

EXAMPLE 185 Synthesis of4-(4-Aminophenyl)-1-methyl-6,7-methylenedioxyphthalazine

Part A:4-(4-Acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylenedioxyphthalazine

An oven dried, 3-necked, 250 mL flask was purged with nitrogen andcharged with 1-(4-acetylaminophenyl)-6,7-methylendioxyphthalazine (1.0g, 3.3 mmole), distilled THF (30 mL) and TMEDA (10 mL). The suspensionwas cooled in an ice bath and treated dropwise over five minutes with anether solution of methyl lithium (9.3 mL of a 1.4M solution, 13 mmole).The dark brown mixture was stirred for 1 h, treated cautiously withwater (5 mL) then dichloromethane (120 mL). The contents of the flaskwere transferred to a separatory funnel, water (100 mL) was added andthe layers were separated. The aqueous phase was further extracted withdichloromethane (50 mL), the extracts combined, washed with brine (100mL), dried (MgSO₄) and evaporated in vacuo. The tan foamy residue wasdissolved in methanol (20 mL), silica gel was added and the solvent wasevaporated to complete dryness. The crude product was chromatographed onsilica gel eluted with EtOAc to afford the addition product a light tancrystalline solid (0.53 g, 50%). Mp 236°-239° C. 200 MHz ¹ H-NMR(CDCl₃); δ7.59 (s, 4H), 7.26 (brs, 1H, NHCOCH₃), 6.75 (s, 1H), 6.73 (s,1H), 6.00 (s, 2H, 0CHO), 5.88 (brs, 1H), 4.31 (q, 1H, J=6.4 Hz,--CHCH₃), 2.60 (s, 3H, COCH₃), 1.48 (d, 3H, J=6.4 Hz, CHCH₃).

Part B:4-(4-Aminophenyl)-1-methyl-6,7-methylenedioxy-1,2-dihydrophthalazine

4-(4-Aminophenyl)-6,7-methylenedioxyphthalazine (600 mg, 2.3 mmol) wassuspensed in THF (25 mL) at 20° C. in an oven dried 3-necked flask underN₂. CH₃ Li (6.5 mL, 9.1 mmol) in ether was added slowly and stirred for30 min. The reaction was quenched by the addition of 1N HCl (50 mL) andthen extracted with EtOAc (30 mL). The organic layer was extracted againwith 1N HCl (100 mL) and then the combined aqueous layers neutralizedwith 1N NaOH. The aqueous mixture was then extracted with CH₂ Cl₂ (3×50mL) and the organic layers combined, dried with K₂ CO₃ and evaporated togive a brown gum. The brown gum was chromatographed on silica-gel 4:1EtOAc/hexane to give a yellow gum (320 mg, 50%). 200 MHz ¹ H-NMR(CDCl₃); δ7.64 (d, 2H), 7.35 (d, 2H), 6.56 (d, 2H), 6.06 (s, 2H), 4.29(q, CH), 1.33 (d, CH₃).

Part C. 4-(4-Aminophenyl)-1-methyl-6,7-methylenedioxyphthalazine

4-(4-Aminophenyl)-1-methyl-6,7-methylenedioxyphthalazine (200 mg, 0.71mmol) and Pd/C (25 mg) were suspended in toluene (15 mL) and heated toreflux under N₂ for 10 h. Upon cooling to 20° C. a beige solid appearedand was collected by filtration. Silica gel chromatography (9:1EtOAc/MeOH) gave a yellow solid, 130 mg, (66%). 200 MHz ¹ H-NMR (CDCl₃);δ7.50 (d, 2H), 7.36 (d, 2H), 6.83 (d, 2H), 6.16 (s, CH₂) 2.93 (s, CH₃).

Modifications and variations of the present invention will be obvious tothose skilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofappended claims.

What is claimed is:
 1. A compound of Formula I: ##STR6## wherein R¹, R³and R⁴ are independentlya) H, b) HO, c) R¹¹ O--, d) halogen, e)C1-C3-alkyl, f) CF₃, g) R¹² CO₂ --, or h) R₁₂ C(O)NH--, with the provisothat no more than two of R¹ -R⁴ can be iodo and that R1-R4 cannot bemixtures of b) and c); R¹ and R², or R² and R³, or R³ and R⁴ can betaken together to bea) --OCH₂ O--, or b) --OCH₂ CH₂ O--; R⁵ and R⁶ areindependentlya) H, b) C1-C6-alkyl, c) C3-C6-alkenyl, d) C3-C6 alkynyl,e) C3-C6-cycloalkyl, f) phenyl or substituted phenyl, where the phenylis substituted with one or two substituents selected from the groupconsisting of C1-C3-alkyl, halogen, R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂-- and CO₂ R¹², or g) phenyl-C1-C3-alkyl or substitutedphenyl-C1-C3-alkyl, where the phenyl is substituted with one or twosubstituents selected from the group consisting of C1-C3-alkyl, halogen,R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂ -- and CO₂ R¹², with the proviso thatR⁵ and R⁶ cannot both be phenyl or substituted phenyl; R⁷ isa) R¹³ R¹⁴NC(O)--, b) R¹³ R¹⁴ NC(S)--, c) R¹³ R¹⁴ NC(NR¹²)--, d) R¹⁵ OC(O)--, e)R¹³ C(O)--, f) R¹³ R¹⁴ NCH₂ C(O)--, g) R¹² O₂ C--(CH₂)_(n) --, h) R¹³R¹⁴ NC(O)--(CH₂)_(n) --, i) NC--(CH₂)_(n) --, j) C3-C6-alkenyl, or k)C3-C6-alkynyl R⁸ and R⁹ are independentlya) H, b) R¹³ R¹⁴ N--, c) R³NHC(NH)--, d) R² HNC(O)--, or e) R² C(O)NH--; R¹⁰ isa) H, b)C1-C3-alkyl, c) halogen, d) R¹² HN--, e) R¹² O--, f) CF₃ --, or g) CO₂R¹² ; R¹¹ is C1-C3-alkyl; R¹² is H or C1-C3-alkyl; R¹³ and R¹⁴ areindependentlya) H, b) C1-C10-alkyl, c) C1-C6-perfluoroalkyl, d)C3-C10-alkenyl, e) C3-C10-alkynyl, or f) C3-C6-cycloalkyl; R¹³ and R¹⁴taken together can be C3-C6-cycloalkyl that includes the nitrogen towhich R¹³ and R¹⁴ are attached; R¹⁵ is C1-C6-alkyl, C3-C6-alkenyl, orC3-C6-cycloalkyl; n is 1 to 6; m is 0 to 2; and pharmaceuticallyacceptable salts thereof; wherein R⁸ and R⁹ both are not H.
 2. Thecompound of claim 1 of Formula I whereinR¹, R.sup.₂, R³ and R⁴ areindependently H, R¹¹ O--, halogen, or C1-C3-alkyl; R² and R³ takentogether can be --OCH₂ O--; R⁷ isa) R¹³ R¹⁴ NC(O)--, b) R¹³ R¹⁴NC(NR¹²)--, c) R¹⁵ OC(O)--, d) R¹³ C(O)--, or e) R¹³ R¹⁴ NC(S)--, R⁸ andR⁹ are independently H, H₂ N--, or CH₃ C(O)NH--; and pharmaceuticallyacceptable salts thereof; wherein R⁸ and R⁹ both are not H.
 3. Thecompound of claim 2 of Formula 1 selected from the group consistingof4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-ethylcarbamoyl-6,7-methylenedioxyphthalazine,4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine,4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,4-(3-aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6,7-methylenedioxyphthalazine,4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylthiocarbamoyl-6,7-methylenedioxyphthalazine,and4-(4-acetylaminophenyl)-1,2-dihydro-1-methyl-6,7-methylenedioxyphthalazine.4. A composition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount for treating a disorder associated withexcessive activation of theα-amino-3-hydroxy-5-methyl-4-isooxazoleproprionic acid (AMPA) subtype ofthe ionotropic excitatory amino acid (EAA) receptors of a compound ofFormula I: ##STR7## wherein R¹, R², R³ and R⁴ are independentlya) H, b)HO, c) R¹¹ O--, d) halogen, e) C1-C3-alkyl, f) CF₃, g) R¹² CO₂ --, or h)R¹² C(O)NH--, with the proviso that no more than two of R¹ -R⁴ can beiodo and that R1-R4 cannot be mixtures of b) and c); R¹ and R², or R²and R³, or R³ and R⁴ can be taken together to bea) --OCH₂ O--, or b)--OCH₂ CH₂ O--; R⁵ and R⁶ are independentlya) H, b) C1-C6-alkyl, c)C3-C6-alkenyl, d) C3-C6 alkynyl, e) C3-C6-cycloalkyl, f) phenyl orsubstituted phenyl, where the phenyl is substituted with one or twosubstituents selected from the group consisting of C1-C3-alkyl, halogen,R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂ -- and CO₂ R¹², or g)phenyl-C1-C3-alkyl or substituted phenyl-C1-C3-alkyl, where the phenylis substituted with one or two substituents selected from the groupconsisting of C1-C3-alkyl, halogen, R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂-- and CO₂ R¹², with the proviso that R⁵ and R⁶ cannot both be phenyl orsubstituted phenyl; R⁷ isa) R¹³ R¹⁴ NC(O)--, b) R¹³ R¹⁴ NC(S)--, c) R¹³R¹⁴ NC(NR²)--, d) R¹⁵ OC(O)--, e) R¹³ C(O)--, f) R¹³ R¹⁴ NCH₂ C(O)--, g)R¹² O₂ C--(CH₂)_(n) --, h) R¹³ R¹⁴ NC(O)--(CH₂)_(n) --, i) NC--(CH₂)_(n)--, j) C3-C6-alkenyl, or k) C3-C6-alkynyl R⁸ and R⁹ are independentlya)H, b) R¹³ R¹⁴ N--, c) R³ NHC(NH)--, d) R¹² HNC(O)--, or e) R₁₂ C(O)NH--;R¹⁰ isa) H, b) C1-C3-alkyl, c) halogen, d) R¹² HN--, e) R¹² O--, f) CF₃--, or g) CO₂ R¹² ; R¹¹ is C1-C3-alkyl; R¹² is H or C1-C3-alkyl; R¹³ andR¹⁴ are independentlya) H, b) C1-C10-alkyl, c) C1-C6-perfluoroalkyl, d)C3-C10-alkenyl, e) C3-C10-alkynyl, or f) C3-C6-cycloalkyl; R¹³ and R¹⁴taken together can be C3-C6-cycloalkyl that includes the nitrogen towhich R¹³ and R¹⁴ are attached; R¹⁵ is C1-C6-alkyl, C3-C6-alkenyl, orC3-C6-cycloalkyl; n is 1to 6; m is 0 to 2; and pharmaceuticallyacceptable salts thereof; wherein R⁸ and R⁹ both are not H.
 5. Acomposition comprising a therapeutically effective amount of thecompound of claim 2 for treating a disorder associated with excessiveactivation of the α-amino-3-hydroxy-5-methyl-4-isooxazoleproprionic acid(AMPA) subtype of the ionotropic excitatory amino acid (EAA) receptorsand a pharmaceutically acceptable carrier.
 6. A composition comprising atherapeutically effective amount of the compound of claim 3 for treatinga disorder associated with excessive activation of theα-amino-3-hydroxy-5-methyl-4-isooxazoleproprionic acid (AMPA) subtype ofthe ionotropic excitatory amino acid (EAA) receptors and apharmaceutically acceptable earlier.
 7. A compound of Formula II:##STR8## wherein R¹, R², R³ and R⁴ are independentlya) H, b) HO, c) R¹¹O--, d) halogen e) C1-C3-alkyl, f) CF₃, g) R² CO₂ --, or h) R¹²C(O)NH--; R¹ and R², or R² and R³, or R³ and R⁴ can be taken together tobea) --OCH₂ O--, or b) --OCH₂ CH₂ O--; R⁵ isa) H, b) C1-C6-alkyl, c)C3-C6-alkenyl, d) C3-C6-alkynyl, e) C3-C6-cycloalkyl, f) phenyl orsubstituted phenyl, wherein the phenyl is substituted with one or twosubstituents selected from the group consisting of C1-C3-alkyl, halogen,R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂ -- and CO₂ R¹², or g)phenyl-C1-C3-alkyl or substituted phenyl-C1-C3-alkyl, wherein the phenylis substituted with one or two substituents selected from the groupconsisting of C1-C3-alkyl, halogen, R¹² HN--, R¹² O--, CF₃ --, R¹¹ SO₂-- and CO₂ R¹² ; R¹¹ is C1-C3-alkyl; R¹² is H or C1-C3-alkyl; R¹⁶ andR¹⁷ are independentlya) H, b) C1-C3-alkyl, c) halogen, d) R¹² O--, e)CF₃ --, or f) --CO₂ R¹² ; R¹⁸ and R¹⁹ are independentlya) H, b) R¹³ R¹⁴N--, c) R¹³ NHC(NH), or d) R¹² CONH--; and pharmaceutically acceptablesalts thereof, with the proviso that R¹⁸ and R¹⁹ cannot both be H. 8.The compound of claim 7 of Formula II whereinR¹, R², R³ and R⁴ areindependently H, R¹¹ O--, halogen, or C1-C3-alkyl; R² and R³ takentogether can be --OCH₂ O--; and R¹⁸ and R¹⁹ are independently H, NH₂ orCH₃ C(O)NH--;and pharmaceutically acceptable salts thereof.
 9. Thecompound of claim 7 of Formula II selected from the group consistingof1-(3-aminophenyl)-6,7-methylenedioxyphthalazine,1-(3-amino-4-methylphenyl)-6,7-methylenedioxyphthalazine,1-(3-amino-4-chlorophenyl)-6,7-methylenedioxyphthalazine,1-(3-aminophenyl)-6-methoxyphthalazine,1-(3-amino-4-methyl-phenyl)-6-methoxyphthalazine,1-(3-amino-4-chloro-phenyl)-6-methoxyphthalazine1-(4-aminophenyl)-6,7-methylenedioxyphthalazine,1-(4-acetylaminophenyl)-6,7-methylenedioxyphthalazine,4-(4-aminophenyl)-1-methyl-6,7-methylenedioxyphthalazine,4-(4-acetylaminophenyl)-1-methyl-6,7-methylenedioxyphthalazine,1-(4-aminophenyl)-7-methoxyphthalazine,1-(4-acetylaminophenyl)-7-methoxyphthalazine,4-(4-aminophenyl)-1-methyl-7-methoxyphthalazine, and4-(4-acetylaminophenyl)-1-methyl-7-methoxyphthalazine.